Addition of Angiotensin Receptor Blockade or Mineralocorticoid Antagonism to Maximal Angiotensin-Converting Enzyme Inhibition in Diabetic Nephropathy

• Published in: Journal of the American Society of Nephrology Vol. 20; no. 12; pp. 2641 - 2650
• Main Authors: MEHDI, Uzma F, ADAMS-HUET, Beverley, RASKIN, Philip, VEGA, Gloria L, TOTO, Robert D
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society of Nephrology 01-12-2009
• Subjects: Adult; Albuminuria - drug therapy; Albuminuria - urine; Angiotensin II Type 1 Receptor Blockers - administration & dosage; Angiotensin II Type 1 Receptor Blockers - adverse effects; Angiotensin-Converting Enzyme Inhibitors - administration & dosage; Angiotensin-Converting Enzyme Inhibitors - adverse effects; Associated diseases and complications; Bicarbonates - blood; Biological and medical sciences; Blood Pressure - drug effects; Clinical Research; Creatinine - urine; Diabetes. Impaired glucose tolerance; Diabetic Nephropathies - drug therapy; Diabetic Nephropathies - physiopathology; Diabetic Nephropathies - urine; Double-Blind Method; Drug Therapy, Combination; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Female; Glycated Hemoglobin A - metabolism; Humans; Hypertension - drug therapy; Hypertension - physiopathology; Hypertension - urine; Kidneys; Lisinopril - administration & dosage; Lisinopril - adverse effects; Losartan - administration & dosage; Losartan - adverse effects; Male; Medical sciences; Middle Aged; Mineralocorticoid Receptor Antagonists - administration & dosage; Nephrology. Urinary tract diseases; Potassium - blood; Renin-Angiotensin System - drug effects; Spironolactone - administration & dosage; Spironolactone - adverse effects; Urinary system involvement in other diseases. Miscellaneous; Endocrinopathy; Kidney disease; Nephrology; Urinary system disease; Enzyme; Mineralocorticoid; Diabetes mellitus; Angiotensin receptor; Urology; Peptidases; Concomitant disease; Antagonism; Peptidyl-dipeptidase A; Hydrolases; Peptidyl-dipeptidases; Diabetic nephropathy; Inhibitor; Inhibition
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/asn.2009070737

Aldosterone promotes glomerular and tubular sclerosis independent of angiotensin II in animal models of diabetic nephropathy. Most human studies testing the renoprotective benefit of adding an angiotensin receptor blocker or a mineralocorticoid receptor antagonist to a regimen based on inhibition of angiotensin-converting enzyme (ACE) used relatively low doses of ACE inhibitors. Furthermore, these studies did not determine whether antiproteinuric effects were independent of BP lowering. We conducted a double-blind, placebo-controlled trial in 81 patients with diabetes, hypertension, and albuminuria (urine albumin-to-creatinine ratio > or =300 mg/g) who all received lisinopril (80 mg once daily). We randomly assigned the patients to placebo, losartan (100 mg daily), or spironolactone (25 mg daily) for 48 wk. We obtained blood and urine albumin, urea, creatinine, electrolytes, A1c, and ambulatory BP at baseline, 24, and 48 wk. Compared with placebo, the urine albumin-to-creatinine ratio decreased by 34.0% (95% CI, -51.0%, -11.2%, P = 0.007) in the group assigned to spironolactone and by 16.8% (95% CI, -37.3%, +10.5%, P = 0.20) in the group assigned to losartan. Clinic and ambulatory BP, creatinine clearance, sodium and protein intake, and glycemic control did not differ between groups. Serum potassium level was significantly higher with the addition of either spironolactone or losartan. In conclusion, the addition of spironolactone, but not losartan, to a regimen including maximal ACE inhibition affords greater renoprotection in diabetic nephropathy despite a similar effect on BP. These results support the need to conduct a long-term, large-scale, renal failure outcomes trial.